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XB130 as an Independent Prognostic Factor in Human Esophageal Squamous Cell Carcinoma

  • Translational Research and Biomarkers
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Adaptor proteins, with multimodular structures, can participate in the regulation of various cellular functions. A novel adaptor protein XB130 has been implicated as a substrate and regulator of tyrosine kinase-mediated signaling and in controlling cell proliferation and apoptosis in thyroid and lung cancer cells. However, its expression and role in gastrointestinal cancer have not been investigated. We sought to determine the role of XB130 in cell cycle progression of esophageal squamous cell carcinoma (ESCC) cells and to examine its expression and effects on the prognosis of patients with ESCC.

Methods

Expression of XB130 in human ESCC cell lines was analyzed by Western blot testing and immunofluorescent staining. Knockdown experiments with XB130 small interfering RNA (siRNA) were conducted, and the effect on cell cycle progression was analyzed. Immunohistochemistry of XB130 for 52 primary tumor samples obtained from patients with ESCC undergoing esophagectomy was performed.

Results

XB130 was highly expressed in TE2, TE5, and TE9 cells. In these cells, knockdown of XB130 with siRNA inhibited G1–S phase progression and increased the expression of p21, the cyclin-dependent kinase inhibitor. Immunohistochemistry showed that 71.2 % of the patients expressed XB130 in the nuclei and/or cytoplasm of the ESCC cells. Further, nuclear expression of XB130 was an independent prognostic factor of postoperative survival.

Conclusions

These observations suggest that the expression of XB130 in ESCC cells may affect cell cycle progression and impact prognosis of patients with ESCC. A deeper understanding of XB130 as a mediator and/or biomarker in ESCC is needed.

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Acknowledgment

Supported in part by Grant-in-Aid for Young Scientists (B) (22791295, 24791440, 23791557) and Grant-in-Aid for Scientific Research (C) (22591464, 24591957) from the Japan Society for the Promotion of Science; and by research grant awards from Kyoto Preventive Medical Center (A.S.).

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Authors and Affiliations

  1. Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan

    Atsushi Shiozaki MD, PhD, Toshiyuki Kosuga MD, Daisuke Ichikawa MD, PhD, Shuhei Komatsu MD, PhD, Hitoshi Fujiwara MD, PhD, Kazuma Okamoto MD, PhD, Daisuke Iitaka MD, Shingo Nakashima MD, Hiroki Shimizu MD, Takeshi Ishimoto MD, Maki Kitagawa MD, Yoshito Nakou MD & Eigo Otsuji MD, PhD

  2. Department of Pathology, Kyoto Prefectural University of Medicine, Kyoto, Japan

    Mitsuo Kishimoto MD, PhD

  3. Latner Thoracic Surgery Research Laboratories, University Health Network Toronto General Research Institute, Toronto, ON, Canada

    Mingyao Liu MD

  4. Department of Surgery, Faculty of Medicine, University of Toronto, Toronto, ON, Canada

    Mingyao Liu MD

Authors
  1. Atsushi Shiozaki MD, PhD
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  2. Toshiyuki Kosuga MD
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  3. Daisuke Ichikawa MD, PhD
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  4. Shuhei Komatsu MD, PhD
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  5. Hitoshi Fujiwara MD, PhD
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  13. Mitsuo Kishimoto MD, PhD
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  14. Mingyao Liu MD
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  15. Eigo Otsuji MD, PhD
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Corresponding author

Correspondence to Atsushi Shiozaki MD, PhD.

Additional information

Atsushi Shiozaki and Toshiyuki Kosuga contributed equally to this work, and both should be considered first author.

Electronic supplementary material

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10434_2012_2474_MOESM1_ESM.pdf

Supplementary Figure 1. Down-regulation of XB130 with siRNA did not affect expressions of p16, p53 and Rb in ESCC cells. Western blotting revealed that expressions of p16, p53 and Rb were not changed by the down regulation of XB130 in TE2, TE5 and TE9 cells. Supplementary Figure 2. Roles of XB130 in apoptosis, migration and invasion of ESCC cells. (A) Down-regulation of XB130 enhanced induced early apoptosis only in TE9 cells. Cells transfected with control or XB130 siRNA were treated with or without staurosporine (STS, 200 nmol/L) for 24 h. Apoptosis was determined by flow cytometry using PI/annexin V double staining. Early apoptosis; annexin V positive/PI negative. Late apoptosis; annexin V positive/PI positive. Mean ± SEM. n = 3. *p < 0.05 (compared with control siRNA). (B) Down-regulation of XB130 partially inhibited cell migration and invasion in ESCC cells. Cell migration and invasion were determined by Boyden chamber assay. Mean ± SEM. n = 3. *p < 0.05 (compared with control siRNA). Supplementary Figure 3. XB130 protein expression in human esophageal epithelia. Immunohistochemistry staining with XB130 monoclonal antibody for human esophageal epithelia. (A) XB130 protein was not detected in non-cancerous esophageal epithelia. (B) The expression of XB130 was identified in normal esophageal glands. Magnification: 200 × . Supplementary Figure 4. XB130 protein expression in human intramucosal ESCC. The expression of XB130 protein was clearly identified in intramucosal carcinoma (A, B). In the same sample, the expression of XB130 protein was identified in intraepithelial lesion of squamous cell carcinoma, whereas there was no expression in non-neoplastic epithelial cells (C, D). (magnification: 200 ×). Supplementary Figure 5. XB130 protein expression in pre cancerous tissue in human esophageal epithelia. The expression of XB130 protein was found in both the nucleus and the cytoplasm in patients with severe dysplasia. Supplementary Figure 6. p21 protein expression in human ESCC. Immunohistochemistry staining with p21 antibody for primary tumor sample of human well differentiated ESCC. The expression of p21 was clearly identified in the nucleus of ESCC. Supplementary Figure 7. Survival curve after curative resection for ESCC. (A) Survival curve of patients with or without nuclear XB130 expression. (B) Survival curve of patients with or without cytoplasmic XB130 expression. Statistical analysis: log-rank test. *p < 0.05 (PDF 415 kb)

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Shiozaki, A., Kosuga, T., Ichikawa, D. et al. XB130 as an Independent Prognostic Factor in Human Esophageal Squamous Cell Carcinoma. Ann Surg Oncol 20, 3140–3150 (2013). https://doi.org/10.1245/s10434-012-2474-4

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  • DOI: https://doi.org/10.1245/s10434-012-2474-4

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